Mineralocorticoid receptor signaling in the microenvironment of dystrophic skeletal muscles


Pre-Clinical Research

Poster Number: 124


Chetan Gomatam, MS, The Ohio State University, Zachary Howard, PhD, The Ohio State University, Jeovanna Lowe, The Ohio State University, Shyam Bansal, PhD, The Ohio State University, Jill Rafael-Fortney, PhD, The Ohio State University

Duchenne muscular dystrophy (DMD) is a fatal disease resulting from the absence of dystrophin that causes chronic striated muscle injury and gradual muscle degeneration, leading to destruction of muscle and eventual loss of life in the mid-twenties. Chronic injury occurs due to cycles of muscle degeneration and regeneration, which leads to overactivation of fibroblasts. Fibroblasts are normally essential for organ structure and wound healing via their ability to temporarily stabilize injury sites by depositing extracellular matrix (ECM) components. However, fibroblasts cause pathogenic fibrosis when overactivated due to excess deposition of ECM that replaces muscle tissue in DMD. We have identified mineralocorticoid receptor (MR) antagonists as a potential therapy to alleviate fibrosis and inflammation in muscular dystrophies. However, effects of MR signaling on fibroblasts and the role of MR in muscle fibroblasts are not known.
Using fluorescence activated cell sorting and gene expression analyses in MR antagonist-treated dystrophic mdx mice and in mdx mice with cell-specific MR conditional knockouts (MRcko), we have begun to explore the fibroblast response to MR signaling in the muscle microenvironment and the role of fibroblast-specific MR. Our recent gene expression microarray of MRcko-mdx mice and RNA sequencing of mdx myeloid immune cells from dystrophic muscles suggest that there is significant crosstalk between immune cells, fibroblasts, and myofibers in DMD. Several genes involved in regulation of extracellular matrix and development of fibrosis were significantly upregulated in myeloid cell-specific MRcko-mdx mice versus myofiber-specific MRcko-mdx mice, including fibronectin, tenascin, and lysyl oxidase. In vivo and in vitro assays combined with genetic approaches will be used to decipher whether MR signaling in the muscle microenvironment has indirect and direct effects on fibroblast activation and function, and whether MR signaling differs between muscle groups and between chronic and acute injury.